Probiotics, Prebiotics, Synbiotics: On microbiomes and the meaning of life

By John F Pohl

http://evolution.berkeley.edu/evolibrary/article/evo_04

“Just as a body, though one, has many parts, but all its many parts form one body, so it is with Christ. For we were all baptized by[c] one Spirit so as to form one body—whether Jews or Gentiles, slave or free—and we were all given the one Spirit to drink. Even so the body is not made up of one part but of many.” 1 Corinthians 12: 12-14 (NIV)

“Again Jesus called the crowd to him and said, “Listen to me, everyone, and understand this. Nothing outside a person can defile them by going into them. Rather, it is what comes out of a person that defiles them.” After he had left the crowd and entered the house, his disciples asked him about this parable. “Are you so dull?” he asked. “Don’t you see that nothing that enters a person from the outside can defile them? For it doesn’t go into their heart but into their stomach, and then out of the body.” Mark 7: 14-19 (NIV)

Human beings, like all complex animals, are fascinating examples of the multi-layering of organic chemistry and biochemistry pathways. Our cells are eukaryotic organisms (that is, our cells, unlike bacteria, have a nucleus and organelles) covered by a lipid bilayer membrane with proteins protruding through in order to allow communication with the outside world via chemical and electrical gradient signatures.

Since our cells are eukaryotes, we apparently have an advantage compared to our prokaryote neighbors (i.e., bacteria) since we have encapsulated organelles and a nucleus, have a larger cell size, and have more genetic information (as in chromosomes filled with DNA) to allow for massive variation during data exchange. One might proudly think that we are a most superior creature. Our eukaryotic cells have come together in a multitude of around 30 trillion to form an adult human. Our cells are a veritable walking coral reef, of sorts, with highly specialized cells working together to allow us to walk, talk, make little ones, and write a paper about our cells. We would appear to be in control…but perhaps not…as we think about the human microbiome.

All sorts of “other” interact with our body on a daily basis, minute by minute, throughout each of our existences on this planet. Billions, if not trillions, of viruses, bacteria, fungi, protists, and the like interact with our body, invade our body, help our body, hurt our body, and even just hang out in our body without ever interacting at all... and we know so little about them. However, these creatures now have been given global terms, including the microbiome (these microbes and their genetic signature) and the microbiota (the taxa identified with these microbes). Research over the past 15-20 years has exploded in this particular area of science, and we are just beginning to understand these creatures, their interactions with us, and what it means to truly be human with billions of organisms constantly interacting with us throughout our body.

Terms and Interactions

Probiotics are essentially commensal bacteria or fungi normally found interacting with humans (such as in the intestine) that function as “good bacteria” or “good fungi.” Certain Lactobacillus, Bifidobacterium, and Saccharomyces species typically are used as probiotics in over-the-counter supplements. Probiotics compete for niche space against pathogenic bacteria and likely have the ability to modulate our immune system for certain diseases. In fact, evidence suggests that the systemic effects of probiotics may be more profound that we realize.

For example, changing the composition of gut bacteria in patients with cystic fibrosis using probiotics may potentially alter the bacteria in the lungs to less pathogenic agents which could improve lung health. One additional point to consider in the realm of probiotics is the use of fecal transplantation, which is the relatively new technique of providing a large-volume stool transplant from a healthy donor to a sick individual via a feeding tube, enema, or endoscopic technique. This technique has been used successfully to treat specific chronic gastrointestinal infections, such as Clostridium difficile, although the therapeutic effect of fecal transplantation for other gastrointestinal diseases (such as Crohn disease and ulcerative colitis) is not entirely clear and not routinely recommended.

Prebiotics are generally defined as non-absorbed substances which promote the growth of “healthy” bacteria in the intestine similar to those bacteria considered probiotics. Fiber sources, cereal grains such as bran, and polysaccharides such as inulin are known dietary prebiotics. Breast milk, already brimming with antibodies to fight infections, has prebiotic potential as infants fed breast milk typically develop intestinal bacteria that are more beneficial in preventing infections compared to those infants fed solely formula.

Synbiotics are simply a combination of pro- and prebiotics. Because there is such a large number of combinations of such products available, it is somewhat unclear as to what clinical benefit synbiotics provide.

Lest we forget, antibiotics are one of major advances in the history of medicine. These are pharmaceutical agents that work via various modes to disrupt cell replication leading to bacterial death. The lay public has likely heard about the tremendous overuse of antibiotics (in humans as well as in farm animals) leading to antibiotic resistance. Additionally, antibiotic use (especially chronic antibiotic use) can disrupt the intestinal microbiome, leading to gastrointestinal infections, such as Clostridium difficile; thus, appropriate antibiotic stewardship is greatly needed worldwide.

Therapeutic Benefits

Whenever a product that is deemed “natural” becomes available in pharmaceutical or over-the-counter dietary forms, it is often assumed that it is “good for you” even by health care professionals. In many ways, the term “probiotic” is problematic in itself as “pro” has the meaning of “on behalf of.” As a result, there really is an over-abundance of inaccurate advertising regarding the benefits of pro-, pre-, and synbiotics. In reality, most of the effects of these agents in healthy individuals likely are negligible.

As a clinician, I find a large amount of the research disjointed and without a clear outcome when I am caring for patients who might benefit from pro-, pre-, or synbiotics. The sheer volume of research in this area is fascinating. A simple search on PubMed for “microbiome” leads to over 26,000 articles while “probiotic” (at the time of this writing) has 17,188 articles, “prebiotic” has 5238 articles, and “symbiotic” has close to 800 articles.

There are two aspects of the microbiome in relation to clinical disease that I can discuss as a pediatric gastroenterologist. First, we need to consider necrotizing enterocolitis (known as NEC) which is a significant cause of death and disability in newborn intensive care units (or NICUs), especially in premature infants. The cause of NEC is unknown; however, its etiology is likely multifactorial, including having a thin bowel wall due to prematurity allowing bacteria to more easily cross into the blood stream, an increased risk of blood clotting of the intestinal blood vessels leading to death of the intestine, and excess growth of potentially dangerous bacteria in the intestine (which is known as “bacterial overgrowth”).

When one considers the aspect of bacterial overgrowth, probiotics may have a purpose in preventing NEC. Indeed, there is evidence that probiotic use in such infants may reduce the incidence of NEC by outcompeting the pathogenic bacteria in the intestine while perhaps also having associated antibacterial properties. Additionally, prebiotics may have a similar benefit when one considers one of the most effective prebiotics, breast milk. Breast milk administration to babies at risk of NEC has been shown to be preventative for NEC occurrence. This begs the question: Why are probiotics not used routinely in premature infants? Unfortunately, this question (like many medical questions) has a very complex answer. Human studies are incredibly difficult to perform. There are many ethical, and in my opinion, potentially moral issues, involved with introducing bacteria into the intestine of potentially critically ill infants. Although some NICUs utilize probiotics on a routine basis, their use is not standardized, and many questions remain about the utility of probiotics in this patient population, including probiotic type, probiotic dosing, duration of probiotic use, and development of algorithms to determine the patient population for which probiotics would be beneficial with a low risk of adverse events.

The other group for which I see probiotics used is in patients with cystic fibrosis. Cystic fibrosis is caused by a mutation of the cystic fibrosis transmembrane conductance regulator gene (or CFTR gene). A simple way of thinking about cystic fibrosis is that mutations of the CFTR gene lead to thickened secretions throughout the body. Cystic fibrosis is associated with progressive lung disease due to thickened fluid and mucous leading to bacterial colonization of the lungs, inflammation, and increasing lung damage. Since the intestinal tract has a large amount of fluid in it, patients with cystic fibrosis have issues related to bacterial overgrowth in the intestine (although the effect is not as severe as in premature infants with NEC). Regardless, probiotics have been studied in patients with cystic fibrosis and are regularly used for specific symptoms of cystic fibrosis, including abdominal pain, diarrhea, poor intestinal absorption, and fat-soluble vitamin malabsorption, although the true effect of probiotic use in many patients with cystic fibrosis is unknown.

Personally, I find the interaction of probiotics in the gut and the potential improvement in lung health of cystic fibrosis very intriguing. The evidence is not very strong as of yet, but there are some preliminary studies which suggest that probiotics given in the intestinal tract may influence the bacteria in the lungs of cystic fibrosis patients leading to less pathogenic bacteria in the lungs and better lung function. The potential association between what cellular signaling occurs between the intestinal tract and lung from probiotic use is fascinating.

Finally, I want to discuss the brain. As a pediatric gastroenterologist, I don’t take care of adults, so I am not intimately familiar with Alzheimer’s disease and other forms of dementia outside of dealing with this issue in my own family. When one considers how the gut microbiome may affect lung function, then one has to wonder if there is an association between what is happening in the intestine and what is happening in the central nervous system, especially in the brain. It turns out that scientists are looking into such an association. No clear link is known; however, certain probiotics can decrease overall inflammation in the elderly, and this finding brings up the question as to whether inflammation in the brain could be reduced in the elderly with use of probiotics. One study using rats suggests that probiotic use in the gut can potentially reduce the risk of other brain disorders, such as anxiety and depression. This aspect is extremely fascinating, but we are a long time away before we truly understand the associations involved.

The Microbiome and Theology

When I first thought about writing this article, I performed a quick search of Google looking for theological considerations of the microbiome. I found almost nothing, and I think this area has much engagement potential for our friends who are theologians. As a physician who is a Christian but not a theologian, I wish to share some ideas that may invite further contemplation.

First, our understanding of the human microbiome appears to put an unusual spin on dualism (the idea that minds are separate from the matter they study, in this case the human body). If one considers the growing corpus of research suggesting bacteria (and possibly fungi or viruses in the microbiome) can affect our mental and emotional health, then these insights may have psychological, evolutionary, ecological, and theological consequences regarding what it means to be human and a child of God.

Second, the idea of the microbiome affecting our personality, our metabolism, and our susceptibility to various diseases puts a new spin on concepts such as the evolutionary arrival of human beings, our absolute freedom, and the extent of our situatedness. That is, we are embedded in various “levels” of dependency on others. For example, our freedom as “individuals” is contingent on our health, and our health is affected by our microbiome (every one of us is reliant on billions of microscopic creatures for our metabolism); yet our microbiome is affected by environmental conditions and cultural practices (such as the geographic and social availability of nutrients, communal traditions for eating and drinking, and the social transmission of microorganisms as can occur when sharing a meal).

What is a Christian perspective on all of the above? I think the idea of the microbiome interacting with our species allows us to be more specific when we consider Paul’s description of each and every person’s part in the “body of Christ.” Yes, we can be the foot, hand, and eye, but perhaps we can be just as important (although not as obvious) as part of the microbiome of humanity. Our daily Christian walk, specifically how we interact with others around us, may appear to be negligible in a grand sense of the history of the human species, butin the context of “Do to others as you would have them do to you,” learning to see others’ bodies as an extension of our own could make a profound impact.

We have learned so much in a relatively short period of time regarding the human microbiome; however, a plethora of unknowns in this field will require further scientific investigation. My personal belief is that eventually we are going to develop individual genomic profiles of a patient’s microbiome in order to treat acute illnesses, but also to prevent chronic disease from occurring or progressing (such as diabetes or coronary artery disease). I also think we are in our infancy in our understanding of the theological impact of the human microbiome, especially in ideas such as “Let us make mankind in our image,” as I believe the microbiome is a synergistic metaphor of how we should love and help each other in our daily existence.

John F. Pohl MD is a professor of pediatrics and a pediatric gastroenterologist at Primary Children’s Hospital (University of Utah) in Salt Lake City, Utah. You can follow John at @Jfpohl on Twitter. John would thank his friend and fellow ASA member, Robert Thoelen, for his helpful edits.